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Prostate Cancer - Diagnosis

by Hans R. Larsen, MSc ChE and William R. Ware, PhD

In a landmark study by Thompson et al published in 2004, 2950 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) underwent end-of-study prostate biopsies regardless of PSA and digital rectal examination (DRE) findings. For those with PSA equal to or less than 4.0 ng/mL at the time of biopsy, about 15% were diagnosed with cancer. The risk increased with PSA levels but was present at even low levels. One critical question concerns the prevalence of insignificant cancers found at biopsy and in the pathological examination of prostates surgically removed. The PCPT data has now been analyzed to examine this question. PSA categories were 0-1.0, 1.1-2.5, 2.6-4. Tumors found at biopsy were categorized as potentially insignificant if they were stage T1c (detected by elevated PSA), negative DRE, PSA density less than 0.15 ng/mL/g, and no evidence of Gleason pattern 4 or 5 in the biopsy cores, Gleason score equal to or less than 6, tumor limited to less than 3 cores with no more than 50% involvement of any core. A second similar set of criteria were also applied. With the above definition of insignificant, the percentages of cancer meeting the criteria for the three strata of PSA were 51.7%, 33.7% and 17.8%. In the PSA range from 0 to 2.5, 39% had insignificant cancer or put another way 61% has significant cancer. The percentages of detected cancers that were significant increased with PSA level and for those with 2.6-4.0 mg/dL, the number was over 82%. These figures did not change much when the data is restricted to the placebo group with a normal DRE.

A subgroup underwent radical prostatectomy. Adverse pathology observed on the prostates removed surgically was defined as any of the following: Gleason score of equal to or greater than 7, extraprostatic extension, seminal vesicle invasion, positive surgical margin, or lymph node metastasis. In men with PSA between 1.1 and 2.5, 37.9% had one or more adverse pathologic features and this increased to 49.1% for the group between 2.6 and 4.0 mg/dL. Extraprostatic extension went up strongly with PSA, as did positive surgical margins. Even when the PSA was below 1.0, 15% had one adverse feature (in this case a Gleason equal to or greater than 7). The presence of adverse pathologic features indicates an enhanced risk of treatment failure. These results strengthen the view that there is no cut-off value for PSA that can provide a high level of comfort if one is worried about having prostate cancer. Furthermore, the real risk of significant disease and disease with adverse features increased monotonically with PSA with no apparent threshold. These results also support the view that the only way to answer the question of the presence of prostate cancer is with a biopsy. But even this statement needs qualification since biopsies also miss cancers. The need for a simple diagnostic test for prostate cancer with a high level of sensitivity and specificity appears urgent. Those who think it is the PSA test are misguided or deceived.
Lucia MS, Darke AK, Goodman PJ et al. Pathologic characteristics of cancers detected in the prostate cancer prevention trial: implications for prostate cancer detection and chemoprevention. Cancer Prev Res 2008 August 1;1(3):167-73
Walsh PC. Re: It's time to abandon an upper limit of normal for prostate specific antigen, J Urol 2009 Mar;181(3):1499

The biopsy procedure can be likened to trying to answer the question - does this blueberry muffin really contain blueberries? The muffin is wrapped in opaque plastic and one proceeds to probe with hollow needles looking for blueberry pulp in the cores. The probability of getting a positive answer when there are in fact blueberries present depends upon the number of needles used or the number of cores taken, the number of blueberries and their distribution and size. In the case of prostate biopsies, only a limited number of needles are used, typically 6 to 18, and zones which statistically are favored for tumors are given more attention. It is not uncommon that an individual will be considered at high risk, for example with a persistent elevated PSA, and yet the first biopsy is negative. A recent single center study from Spain examined the yield of positive cancer diagnosis with a third, fourth and fifth biopsy on patients who came up negative after two. Indications for performing a biopsy on this subgroup included persistent elevated PSA (greater than 4.0 ng/mL, persistent suspicious DRE, PSA velocity greater than 0.75 ng/mL/year, or the finding of precancerous pathology in prior biopsy. The results are interesting. On the third biopsy 15 cancers were found in 61 patients. The fourth biopsy found 5 cancers in 14 patients, and the fifth found 1 cancer in 2 patients. The classical six- needle biopsy was used on 25 patients and an extended 18-needle protocol was used for the balance. Thus out of 61 patients undergoing 3 to 5 biopsies, 21 were diagnosed with prostate cancer (34%). In other words, this group of 61 patients had had two negative biopsies and for those went on to have additional biopsies, over a third had prostate cancer. For those who went on to have a radical prostatectomy, examination of the prostate revealed that all had clinically significant disease. The authors comment that performance of the third, fourth and fifth biopsies were in fact unnecessary in retrospect in 29% of the patients, based on a Gleason score of equal to or less than 5 observed at biopsy. The patients undergoing the third biopsy had a range of PSA from 5.2 to 120 ng/mL. A suspicious DRE suggested the presence of only 4 out of 15 cases where tumors were found.

A limitation with this study is that not all those with a negative first biopsy went on to have additional procedures until either cancer is detected or four or five have been performed. In this study, out of 2457 first biopsies, 810 were positive but of the remaining 1647, only 306 went on to the second biopsy which incidentally had a 29% yield of positive diagnosis. Those encouraged having repeat biopsies presented with risk patterns suggesting that cancer had been missed. This pattern repeated with the majority of individuals having negative results not having additional biopsies. On the third round, only 61 out of 220 had biopsies, with 15 positive results. For the fourth round, only 14 out 146 had biopsies, with 5 positive results, and finally in the fifth round, only 2 had biopsies with one positive result. No information was provided on the prevalence of strong indications in those with a negative biopsy at each stage in the series. Nevertheless, the results are suggestive of large numbers of cancers being missed even in repeat biopsies. The design of this study is quite different from a study reported in 2001, where all participants had agreed to up to 4 biopsies if no cancer was found after the first. The first biopsy yielded 22% positives, the second 10%, the third 5% and the fourth 4%. This study used an 8-needle protocol. Thus in the Spanish study, presumably there was some selection for high-risk candidates for each additional biopsy since they found much higher percentages of positive results.

Presumably, when a patient is told that his first biopsy is negative, he is also told that while it is unlikely that he has cancer, the probability is still significant. When a second biopsy is suggested, it is because there are clinical indications that there is a high probability cancer is present, frequently because of a persistently elevated PSA. It is nevertheless interesting that it can be missed in multiple biopsies. Thus what is held up as the gold standard in prostate cancer diagnosis is not quite 24-caret. We all, including the urology community, eagerly await both screening and diagnosis protocols that come closer to perfection. What is unfortunate is that so many individuals think that perfection has already been attained.
Bahilo Mateu MP, Ramirez BM, Trassierra VM, Di Capua SC, Arlandis GS, Cruz Jimenez JF. [Clinical features and histopathology of prostate cancer diagnosed from the third biopsy]. Actas Urol Esp 2008 November;32(10):961-7
Djavan B, Ravery V, Zlotta A et al. Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol 2001 November;166(5):1679-83

PSA velocity is used to increase the power of PSA screening. But PSA also tends to increase with prostate size, and an increasing prostate size accompanies benign prostatic hyperplasia (BPH). Thus the question of potential confounding. A study by Loeb et al just published in The Journal of Urology addresses this concern. The researchers identified 242 men without prostate cancer from the Baltimore Longitudinal Study of Aging who had 2 or more serial pelvic MRI studies and contemporaneous PSA tests. Prostate volume was estimated from MRI images and the median PSA was 0.9 ng/mL with a mean of 1.3 ng/mL. During the 4.2 years median follow-up, the median rate of prostate volume change was 0.6 cc/year whereas the median PSA change was 0.03 ng/mL per year. Prostate growth rates as high as 10 cc per year were encountered, and yet PSA velocity was less that 0.1 ng/mL per year in most men and showed no correlation with prostate volume. The authors point out that the National Comprehensive Cancer Network now recommends that a prostate biopsy would be considered for men with PSA equal to or less than 2.5 ng/mL if the PSA velocity were greater than 0.35 ng/mL per year. The results of the study by Loeb et al suggest that PSA changes greater than 0.35 ng/mL per year are unlikely to be due to prostate volume changes. These results suggest that progressing BPH is not a confounding factor when PSA velocity is used to indicate a probability of prostate cancer high enough to warrant a recommendation of a biopsy. An editorial by Westphalen which is at the end of the paper by Loeb et al points out that in addition, there is a study in which PSA velocity correlated with MRI findings of malignancy but not BPH which also supports the use of PSA kinetics as a tumor marker. Westphalen suggests that the study of Loeb et al adds to others to provide added evidence for the use of PSA velocity not only in determining prostate cancer aggressiveness but also to aid in biopsy decisions.
Loeb S, Kettermann A, Carter HB, Ferrucci L, Metter EJ, Walsh PC. Does prostate growth confound prostate specific antigen velocity? Data from the Baltimore longitudinal study of aging. J Urol 2008 October;180(4):1314-7

The famous Prostate Cancer Prevention Trial (PCPT) found that 17% of patients with a total PSA between 1.1 and 2.0 ng/mL and 23.9% with total PSA between 2.1 and 3 ng/mL had prostate cancer as detected by biopsy. This prompted the suggestion that the threshold for biopsy be reduced, but the counter argument is always that this will result in a large number of biopsies which in retrospect will turn out to have been unnecessary. This is the inevitable result of having a marker, i.e. PSA, the level of which is associated with a continuously increasing risk of prostate cancer. In fact, there is no safe total PSA level below which prostate cancer does not exist. Since the publication of the PCPT there has been renewed interest in improving the selection process among men with PSA equal to or less than 2.5 ng/mL in order to reduce the number of unnecessary biopsies. If a patient with PSA equal to or less than 2.5 ng/mL has a suspicious digital rectal examination (DRE) then this is generally considered sufficient reason for recommending a biopsy, but when the DRE is unremarkable, there is obviously a problem and the need for novel biomarkers for this subgroup.

A study by Waltz et al has just been published in the journal Cancer which examines the ability of the % free PSA to stratify patients with PSA equal to or less than 2.5ng/mL in order to aid in the decision regarding the recommendation of a biopsy. Since the probability of prostate cancer in this group is about 17%, the objective was to find a way of identifying those most likely to actually have the disease. Between 1999 and 2006, 7880 consecutive men underwent an initial biopsy at two European centers (Hamburg and Milan). Of the total cohort, 1036 had total PSA equal to or less than 2.5 ng/mL. For patients in this subgroup with an unremarkable DRE, 19% had prostate cancer at biopsy whereas overall the rate in the subgroup was 23%. The researchers comment that this is somewhat higher than would be predicted from the PCPT and that this may be due to the nature of the cohort which was referred on the basis of abnormal or suggestive PSA behaviour. The present study also used more biopsy cores as compared to the PCPT study.

The % free PSA was found to provide considerable discrimination. For men with an unremarkable DRE, those with % free PSA equal to or less than 14%, 49% had prostate cancer, whereas for those with %free PSA equal to or greater than 28%, only 9% had prostate cancer. This unfortunately leaves a grey area of greater than 14% to less than 28% free PSA. For the entire group which included men with suspicious DRE, these same two cut-offs found 59% and 13% with prostate cancer. The authors point out that the finding that the % free PSA was highly useful in identifying patients with prostate cancer was also observed in a study by Catalona et al in a group with total PSA between 2.5 and 4.0 ng/mL. Also in studies that examined the performance of free PSA at initial biopsy, repeat biopsy and saturation biopsy, % free PSA was the strongest predictor of prostate cancer. However, a Korean study found that for men 50 to 65 years of age with an unremarkable DRE and PSA between 4.0 and 10.0, % free PSA did not add diagnostic advantage.

Walz et al also examined the fraction of cancers detected in the equal to or less than 2.5 ng/mL group that were deemed clinically significant among the patients undergoing a radical prostatectomy. Despite the favourable total PSA range of this cohort, 16% of the cancers had established extracapsular extension or seminal vesicle invasion and 35.6% had a pathological Gleason score of 3 + 4. It was thought that this subgroup undergoing surgery was representative of the total cohort. The authors comment that the surprisingly elevated proportion of unfavourable pathologic characteristics indicates that low total PSA values are neither indicative of nonexistent cancer nor a favourable pathology. Obviously, the need to replace PSA and even its variants with a definitive yes or no marker for prostate cancer is urgent, but it must be recognized that even the biopsy misses a significant number of cancers. We have come a long way in this field, but we appear to have a long way to go.
Walz J, Haese A, Scattoni V et al. Percent free prostate-specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower. Cancer 2008 Nov 15; 113(10):2695-703
Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997 May 14;277(18):1452-5
Jeong IG, Lee KH. Percent free prostate specific antigen does not enhance the specificity of total prostate specific antigen for the detection of prostate cancer in Korean men 50 to 65 years old: a prospective multicenter study. The Journal of Urology 2008 January;179(1):111-6

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Prostate cancer screening in men over 75 years
DURHAM, NC. Recent evidence shows that men older than 75 years are frequently screened for prostate cancer, despite current guidelines suggesting they are unlikely to benefit from treatment as the disease develops slowly in this age group. Rates of prostate specific antigen (PSA) testing in the US were examined by researchers from Duke University Medical Center. The team took data from national surveys of physician-reported information carried out from 1999 to 2002. They found that 14.1 per cent of all PSA tests during this time involved men over 75 years. Among men of this age, 27.8 per cent underwent PSA testing - a greater proportion than in any other age group. Urologists were more likely to initiate the tests than non-urologists. This confirms patient-reported data; say the team, adding that the presence of a testing laboratory on-site is significantly linked to the likelihood of testing. Excessive PSA testing has direct and indirect costs, and reflects an inefficient allocation of resources, they conclude.
Scales, C. D. et al. Prostate specific antigen testing in men older than 75 years in the United States. The Journal of Urology, Vol. 176, August 2006, pp. 511-14

A rational approach to prostate cancer treatment
TORONTO, CANADA. Dr. Laurence Klotz of the University of Toronto believes that localized prostate cancer is overtreated and that many men with "good risk" prostate cancer can avoid radical intervention (radiation or prostate removal) and still live long enough to die of causes other than prostate cancer. Dr. Klotz recently reported on an ongoing study involving 299 men over the age of 70 years with prostate cancer. At the start of the study in 1995 the men had a PSA (prostate specific antigen) value below 15 ng/mL, a Gleason score of 7 or less, and their cancer rated as stage 2b or less. The men were all placed under active surveillance, which included frequent PSA measurements and a repeat biopsy at 12-18 months after initial diagnosis.

Dr. Klotz believes that the time it takes for the PSA level to double is a good indicator of the aggressiveness of the cancer. If the PSA level doubles in less than 2 years or progression is noted on repeat biopsy or digital rectal examination, then the patient should be offered radical intervention. The PSA doubling time should be based on 3 separate measurements during a minimum of 6 months and the final value should be greater than 8 ng/mL before radical intervention is considered.

The median PSA doubling time (DT) among the 299 patients was 7 years and 42% of the men had a DT of greater than 10 years. Only 21% had a DT less than 3 years. Only 2 patients died from prostate cancer during the first 5 years and after 8 years of follow-up the prostate cancer specific mortality in the group was only 1%. About 60% of the patients remained on active surveillance after 55 months, with the remaining opting for radical therapy either because of diagnosed progression or by personal preference. Dr. Klotz concludes that active surveillance with selective delayed intervention in patients whose PSA DT is less than 3 years may be a practical compromise between across-the-board radical therapy for all patients with localized prostate cancer and watchful waiting with palliative therapy only.
Klotz L. Active surveillance with selective delayed intervention: using natural history to guide treatment in good risk prostate cancer. Journal of Urology, Vol. 172, November 2004, pp. S48-S51

Hand-held scanner for cancer.
Researchers at the University of Bologna have developed a hand-held scanner, similar to those used in airports, which can be used to detect cancer. Apparently cancer tumours create a strong interference at 400 mega hertz when exposed to a weak microwave field emitted by the scanner. Preliminary trials have shown that the scanner can detect prostate cancer with an accuracy of 93% and breast cancer with an accuracy of 66%. Trials for lung, stomach, liver, and colorectal cancers are underway and it is hoped that the scanner can be made commercially available later this year.
New Scientist, June 14, 2003, p. 15

New test predicts the risk of prostate cancer
SEATTLE, WASHINGTON. Researchers at the Pacific Northwest Research Institute and Baylor College of Medicine report the development of a promising new method for determining prostate cancer risk and the risk of metastasis. The researchers compared the DNA spectra (Fourier transform-IR spectra) of prostate tissue taken from younger men (aged 16 to 36 years) and older men (aged 55 to 80 years) as well as prostate tissue spectra from older men with prostate cancer and older men without prostate cancer. They found that there was a highly significant increase in DNA damage (8-hydroxypurine lesions) with advancing age. This damage could be estimated by measuring the concentration of 8- hydroxyguanine in prostate tissue from young and older men. It is known that 8-hydroxyguanine is formed when DNA is attacked by free radicals, specifically hydroxyl radicals.

The researchers also found that they could easily distinguish DNA spectra from older men without prostate cancer from those of older men with prostate cancer. They speculate that the new test may be able to predict the risk of a man developing prostate cancer by determining the extent of free radical damage at any particular point in time. Perhaps the most exciting discovery was the ability of DNA spectra analysis to determine whether the cancer had metastasized well before any damage to other organs actually had occurred.

The researchers conclude that prostate cancer is largely caused by free radical attacks on both the base and backbone structure of DNA. They suggest that an increase in the intake of such dietary antioxidants as vitamin E, lycopene and polyphenols may inhibit the development of prostate cancer.
Malins, Donald C., et al. Cancer-related changes in prostate DNA as men age and early identification of metastasis in primary prostate tumors. Proceedings of the National Academy of Sciences, Vol. 100, No. 9, April 29, 2003, pp. 5401-06

Editor's comment: Vitamin-C (ascorbic acid) is also an effective scavenger of hydroxyl radicals and helps prevent the formation of 8-hydroxyguanine.

Thyroid hormone and prostate cancer
NEW YORK, NY. Prostate cancer usually progresses very slowly and in many cases, especially among older men, requires no other treatment than "watchful waiting". The problem, of course, is to identify those cases that do require aggressive treatment (surgery and radiation) in order to prevent metastasis.

Researchers at Mount Sinai School of Medicine now report that the thyroid hormone, triiodothyronine (T3), may be a useful marker for prostate cancer aggressiveness. It is well established that T3 is required for the growth of prostate cancer cells in vitro. The researchers measured T3 levels in 208 men aged 46 to 96 years. Twenty of the men had an enlarged prostate (benign prostatic hyperplasia or BPH), 161 had localized prostate cancer, and 27 controls had neither BPH nor prostate cancer. The researchers found that men with BPH had significantly higher levels of T3 than did the controls and the prostate cancer patients. Prostate cancer patients also had significantly higher levels than the controls, but lower levels than the men with BPH.

The researchers conclude that T3 may be a useful biomarker for prostate cancer, but that more work is required to definitely establish this. They also suggest that new therapies for BPH and prostate cancer could perhaps be directed towards inhibiting the mitogenic (cell dividing) effects of T3.
Lehrer, Steven, et al. Serum triiodothyronine is increased in men with prostate cancer and benign prostatic hyperplasia. Journal of Urology, Vol. 168, December 2002, pp. 2431-33

Prostate biopsies often unnecessary
SHREVEPORT, LOUISIANA. It is common practice to perform a biopsy of the prostate on men whose PSA (prostate specific antigen) level exceeds 4.0 ng/mL. The results of the biopsy, which is expensive, uncomfortable and anxiety-provoking, are negative in most cases (65 to 85 per cent negative) indicating that no cancer is present. Urologists at the Louisiana State University point out that acute prostatitis (inflammation of the prostate gland) and benign prostatic hypertrophy (enlarged prostate) can also give high PSA readings. They now report on a just completed trial designed to determine if men with chronic prostatitis also have high readings and if so, how often these abnormal readings actually are an indication of prostate cancer.
Their trial involved 95 men who had been diagnosed with chronic prostatitis and who had an elevated PSA level (average of 8.48 ng/mL), but no abnormalities in digital rectal examination. The men were all assigned to a four-week course of antibiotics (fluoroquinolones or doxycycline) and anti-inflammatories (ibuprofen or celecoxib). At the end of the four weeks 44 of the men (46.3 per cent) had a PSA level of less than 4 ng/mL (mean of 2.48 ng/mL) and were deemed to be free of prostate cancer. The remaining 51 men underwent double sextant transrectal ultrasound guided biopsy. Thirteen patients (25.5 per cent) were found to have prostate cancer, 37 (72.5 per cent) had chronic inflammation, and one patient had an enlarged prostate. The researchers conclude that treatment of chronic prostatitis in men with high PSA levels can substantially reduce the need for biopsies. It is of interest to note that the PSA levels in the men eventually diagnosed with prostate cancer only declined from an average of 8.32 to 7.92 ng/mL after four weeks of antibiotic therapy. Editor's Note: The moral of this story is that one should always ensure that one does not have acute or chronic prostatitis before submitting to a prostate biopsy.
Bozeman, Caleb B., et al. Treatment of chronic prostatitis lowers serum prostate specific antigen, Journal of Urology, Vol. 167, April 2002, pp. 1723-26

PSA Screening revisited
BOSTON, MASSACHUSETTS. Dr. Michael Barry of the Harvard Medical School and the Massachusetts General Hospital provides an excellent review of the current status of PSA screening for prostate cancer. Dr. Barry starts out by posing the question "Should a 65-year-old man with no risk factors for prostate cancer except his age and with a normal digital rectal examination undergo a PSA (prostate-specific- antigen) test?" Dr. Barry points out that whether or not to have a PSA test is controversial because of the following:

  • No randomized clinical trials have ever demonstrated that early detection and aggressive treatment of prostate cancer reduce mortality;
  • The treatments usually mobilized after a positive PSA test and biopsy (radical prostatectomy, radiation therapy or castration) are associated with severe side effects including impotence and incontinence.

He also emphasizes that the PSA test is not that accurate. A recent large-scale trial showed that using a cut-off point of 4.0 ng/mL would pick up 46 per cent of cancers that would occur within the next ten years with an accuracy of 91 per cent. The average age of the test group was 63 years. Among older men with benign prostatic hyperplasia (enlarged prostate) the accuracy may be as low as 54 per cent leading to many unneeded biopsies and much unwarranted anxiety. It is estimated that 75 per cent of men undergoing a prostate biopsy because they have PSA levels between 4 and 10 ng/mL do not have cancer. On the other hand, there is also a 10 per cent chance of harbouring cancer even though the biopsy shows nothing.
There are currently at least two large-scale trials underway to determine whether PSA screening is beneficial or harmful overall. However, the results of these trials are not expected until the year 2009. In the meantime Dr. Barry recommends that men aged 50 to 75 years of age (with no established risk factors) should be made aware of the availability of the PSA test and its potential harms and benefits so that they can make an informed choice about having the test. They should receive information on the following points:

  • the likelihood that prostate cancer will be diagnosed;
  • the possibilities of false negative and false positive results;
  • the anxiety associated with a positive test;
  • the uncertainty regarding whether screening reduces the risk of death from prostate cancer.

Several studies have shown that providing this information significantly reduces the proportion of men who decide to be tested.
Barry, Michael J. Prostate-specific-antigen testing for early diagnosis of prostate cancer. New England Journal of Medicine, Vol. 344, May 3, 2001, pp. 1373-77

Should men be screened for prostate cancer?
MONTREAL, CANADA. Physicians in North America are becoming increasingly enthusiastic about screening men for prostate cancer. Prostate cancer is now the second most common cancer among Canadian men and is second only to lung cancer in cancer mortality. The two screening tests commonly used are the digital rectal examination (DRE) and the prostate-specific antigen (PSA) blood test. Recently some doctors have been warning against the wholesale use of screening tests. Dr. Kenneth Marshall of the Queen Elizabeth Hospital in Montreal emphasizes that obtaining the patient's informed consent prior to testing is essential. This is because the PSA test in particular often gives a false reading. This can lead to dangerous, invasive biopsies, and subsequent even more dangerous surgery and radiation treatment. It is estimated that 30 per cent of men undergoing radical prostate surgery become impotent, five to six per cent become incontinent and about one per cent die of the operation. Dr. Marshall concludes there is, as yet, no evidence that screening for prostate cancer actually saves lives - a view supported by many European urologists. He also points out that screening and biopsies may actually do more harm than good in cases where the tumor might have remained dormant or only grown very slowly.
Marshall, Kenneth G. Screening for prostate cancer. Canadian Family Physician, Vol. 39, November 1993, pp. 2385-90

Prostate cancer reaching epidemic proportions
LONDON, ENGLAND. More than 100,000 new cases of prostate cancer are now detected in the U.S.A. and about 33,000 American men die from this disease each year. In the U.K. prostate cancer claimed 9,400 lives in 1992. The cause of the rise in cases is unknown. Alcohol and smoking are not implicated, but diet may well be. Thus the incidence amongst men eating a typical western diet is about 100 per 100,000 as compared to 6 per 100,000 in the Far East. Many men are unaware that they have a prostate tumour. As a matter of fact, latent prostate cancers are found in more than 70% of men over the age of 80, but are not the cause of their death. Recent publicity in the U.S.A., fuelled by the treatment of Senator Robert Dole for prostate cancer, has heightened the awareness of the disease. The total research budget for prostate cancer in the U.S.A. has been increased from $10 million to $24 million annually and all men are now advised to have a rectal examination and a PSA (prostate specific antigen) test every year. While this is expected to detect about 30 to 40% more cancers some medical doctors are sounding a warning: many men have no complications from their prostate tumour and go on to die of unrelated causes - is it right to affect the quality of their lives by telling them that they have prostate cancer?
Siddall, Rhonda. Time to screen for prostate cancer? New Scientist, February 6, 1993, pp. 27-30

Is screening for prostate cancer worthwhile ?
TORONTO, CANADA. The controversy over the benefits of screening for prostate cancer rages on. Now researchers at the University of Toronto have concluded that testing men with no overt symptoms of prostate cancer is inadvisable. They found that screening often precipitates invasive procedures and that the overall effect on quality of life is negative. Specifically, they found that a one-time screening with prostate-specific antigen (PSA) or transrectal ultrasound (TRUS) resulted in only a very small increase in life expectancy in randomly selected men between 50 and 70 years of age. The increase in life expectancy was far outweighed by a net loss in the quality of life due to complications (impotence, incontinence, rectal injuries) occurring during invasive testing procedures and surgery. Screening with a digital rectal examination (DRE) produced no reduction at all in mortality from prostate cancer.
Krahn, Murray D., et al. Screening for prostate cancer: a decision analytic view. Journal of the American Medical Association, Vol. 272, No. 10, September 14, 1994, pp. 773-80

Are prostate cancer rates really growing?
DETROIT, MICHIGAN. The incidence of prostate cancer has seemingly grown rapidly in recent years. In the Detroit area an increase in invasive prostate cancer of 72 per cent has been observed between 1988 and 1991. Researchers at the Michigan Cancer Foundation now believe that the observed increase is due not to the fact that more men get prostate cancer, but rather to a much more widespread use of the prostate-specific antigen (PSA) test. They point out that the use of the PSA test almost quadrupled in the period 1990 to 1992. This rise in test volume is paralleled by a dramatic increase in the rate of radical prostate surgery (prostatectomy) which also quadrupled in the Detroit area between 1987 and 1991. The researchers believe that the "rise" in prostate cancer with the advent of the PSA test is analogous to the "rise" in breast cancer coinciding with the widespread use of mammography. They also point out that the benefit of aggressive local therapy such as prostatectomy as a cure for prostate cancer remains uncertain.
Demers, Raymond Y., et al. Increasing incidence of cancer of the prostate. Archives of Internal Medicine, Vol. 154, June 13, 1994, pp. 1211-16

Screening for prostate cancer not recommended
HOUSTON, TEXAS. Over 165,000 new cases of prostate cancer were diagnosed among men in the United States in 1993 and 35,000 died from the disease. The increased use of screening tests has long been advocated by the medical community as a means of lowering the death toll. Now researchers at the University of Texas have reached the clear conclusion that periodic screening of men with no other symptoms of prostate cancer is not recommended. They base their conclusion on the fact that there have never been any medical trials which showed that early diagnosis increases length of survival or quality of life. Early detection of microscopic cancers may lead to invasive biopsies and treatments which in turn can result in impotence, incontinence and even death. A recent study found that even with the "best possible" treatment (radical prostatectomy and radiation) a patient with a nodule identified by DRE (digital rectal examination) would have been better off if the nodule had been left alone. Other studies have shown that watchful waiting is a reasonable clinical management strategy if a prostate nodule is found. The researchers conclude that when quality-of-life factors are considered, screening men for prostate cancer is not indicated.
Cantor, Scott, B., et al. Prostate cancer screening: a decision analysis. The Journal of Family Practice, Vol. 41, No. 1, July 1995, pp. 33-41

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Cancer screening comes under increasing scrutiny
BOSTON, MASSACHUSETTS. Many cancer researchers are becoming concerned about the development of more and more sophisticated screening tests. Professor Suzanne Fletcher, MD of the Harvard Medical School says "Our tests and technology may have outstripped our ability to distinguish lesions that look like cancer under the microscope but don't act like it." Other researchers point out that 50 per cent of men have signs of prostate cancer, but nevertheless die from other causes. Similarly, 20 to 30 per cent of women have signs of breast cancer when autopsied but only 3 to 4 per cent of all women actually die of breast cancer. The criticism is particularly heavy when it comes to the prostate-specific antigen (PSA) test. Dr. Barnett Kramer, MD of the National Cancer Institute points out that the rate of prostate cancer diagnosis is going up faster than any other cancer on record and the rate of prostate surgery (prostatectomy) is following right along. Complications of impotence, incontinence, and bowel dysfunction after surgery "are on the order of tens of percents" says Dr. Robert Nease of the Washington University Medical School in St. Louis. Dr. Nease concludes "That's a pretty steep price to pay for unproven benefits."
Holzman, David. Screening tests pick up too many indolent cancers. Journal of the National Cancer Institute, Vol. 87, No. 20, October 18, 1995, pp. 1506-07

Accuracy of PSA test questioned
DALLAS, TEXAS. The PSA (prostate-specific antigen) test is commonly used to screen men for prostate cancer. A PSA level of greater than 4.0 ng/mL is generally considered indicative of possible prostate cancer and often triggers an invasive and potentially dangerous biopsy (transrectal ultrasound-guided prostate biopsy). Now researchers at the Dallas Veterans Affairs Medical Center report that a single PSA test may not be reliable enough to serve as a basis for the biopsy decision. Their study involved 295 men who had had a PSA test twice within a period of 90 days. The researchers found that 30 per cent of the patients tested had a PSA difference of more than 1 ng/mL between the two measurements. They conclude that 10 per cent of all patients having a single PSA test would be told either that everything was OK when in fact they might have cancer or be subjected to an unnecessary biopsy. The researchers recommend that physicians make up their own mind as to the level of error they are comfortable with and then repeat the test accordingly. For instance, if a doctor is only willing to accept a 20 per cent or lower probability of being wrong he would repeat the test if the first PSA test gave a value between 2.3 and 8.6 ng/mL. If however, he was willing to accept a 50 per cent risk of being wrong he would only need to repeat tests with values between 3.5 and 4.9 ng/mL. Further statistical evaluation of the data collected by the researchers confirmed that PSA values tend to increase with age from a mean of 1.4 ng/mL between 40 and 50 years of age to a mean of 3.6 ng/mL for men aged 70 to 80 years. The researchers also found that a standard digital rectal examination (DRE) correlates quite well with the PSA test. Men with a normal prostate according to the DRE test had a mean PSA level of 2.44 ng/mL while men with a suspected cancerous tumor on the prostate (according to the DRE test) had a mean PSA level of 3.73 ng/mL. The researchers question the validity of using one standard value (4.0 ng/mL) as a cutoff point to determine if a biopsy is needed. They suggest that the cutoff point should depend on the patient's age with 2.5 ng/mL being the cutoff point for men 40 to 50 years old rising to 6.5 ng/mL for men 70 to 80 years old.
Roehrborn, Claus G., et al. Variability of repeated serum prostate-specific antigen (PSA) measurements within less than 90 days in a well-defined patient population. Urology, Vol. 47, No. 1, January 1996, pp. 59-66

More tests lead to more surgery
PORTLAND, MAINE. Physicians have long been puzzled why some areas of the New England states have very high rates of heart surgery while others have relatively low rates. Now researchers at the Maine Medical Center report that the amount of heart surgery (bypass surgery and angioplasty) done in an area is almost entirely dependent upon how much diagnostic testing is done in that area. In other words, it bears little or no relation to the actual prevalence of heart disease. The researchers found a strong linear relationship between the number of stress tests done in a certain geographical area and the number of subsequent angiography examinations and surgical interventions. This relationship could only be explained by concluding that more testing leads to more surgery. Other New England researchers have arrived at a similar conclusion and have also discovered that more mammography leads to more biopsies and more breast surgery, that more spine x-rays lead to more back surgery, and that more prostate biopsies and most likely more PSA tests lead to more radical prostatectomies. The researchers conclude that "how much disease is diagnosed depends on how hard one looks." They also suggest that physicians should recognize that just as more therapy may be harmful so may more diagnostic tests. The total Medicare billings by American physicians in 1993 for diagnosis and treatment of coronary heart disease exceeded one billion dollars. Medical researchers estimate that 80 per cent of all angiographic procedures are inappropriate and that half of all bypass operations performed in the United States are unneccessary or of no benefit.
Wennberg, David E., et al. The association between local diagnostic testing intensity and invasive cardiac procedures. Journal of the American Medical Association, Vol. 275, No. 15, April 17, 1996, pp. 1161-64
Verrilli, Diana and Welch, H. Gilbert. The impact of diagnostic testing on therapeutic interventions. Journal of the American Medical Association, Vol. 275, No. 15, April 17, 1996, pp. 1189-91

Screening for prostate cancer comes under fire - again!
BRISBANE, AUSTRALIA. The controversy over the routine screening of healthy men for prostate cancer using the PSA (prostate specific antigen) test continues. Now Australian medical doctors and researchers have come out strongly against the practice. The Australian team estimates that if 100,000 men over 50 years of age are screened with the PSA test, about 15,000 will show a positive result, i.e. possible cancer. These 15,000 men will likely have a biopsy which, in itself, is by no means without danger. Of the 15,000 about 4,500 will have a positive biopsy result and will presumably be exposed to further treatment in order to "cure" the cancer. The remaining 10,500 will suffer considerable anxiety while waiting for their biopsy results. The researchers point out that there has been no scientifically valid studies which prove that treatment is more beneficial than no treatment or that screening can extend or improve quality of life. The preferred treatments, however, have very serious side effects. It is estimated that 60 to 90 per cent of men undergoing radical prostatectomy become impotent while 30 to 40 per cent develop some degree of incontinence. Between 40 and 70 per cent of men exposed to radiotherapy also develop impotence. The researchers suggest that routine screening for prostate cancer is comparable to screening for lung cancer. Even though lung cancer kills five times more men than does prostate cancer nobody advocates a routine screening program for lung cancer - for the simple reason that no effective treatment is available for this disease. The researchers conclude that screening men with no other symptoms of prostate cancer is inadvisable.

In a separate research paper Dr. Brian Cox of the Otago Medical School in New Zealand echoes the Australians' recommendation and points out that no proper trials have ever shown that screening has an effect on prostate cancer mortality. He concludes that recommending asymptomatic patients have a PSA test is unethical.
Hirst, Geoffrey H.L., et al. Screening for prostate cancer: the case against. Medical Journal of Australia, Vol. 164, March 4, 1996, pp. 285- 88
Cox, Brian. Prostate cancer screening is experimental. New Zealand Medical Journal, Vol. 109, March 8, 1996, pp. 63-4

New early warning signal for prostate cancer
BOSTON, MASSACHUSETTS. Researchers at the Harvard Medical School report that they have discovered a new diagnostic test which will predict men's risk of prostate cancer years before the cancer actually develops. Their discovery is part of the ongoing Physicians' Health Study which was started in 1982 and involves almost 15,000 physicians. By March 1992 520 cases of prostate cancer had occurred among the physicians. In 152 of these cases enough blood plasma had been collected in 1982 to perform analyses for the content of IGF- I (insulin-like growth factor-I). These analyses were done in 1997 and the results compared to analyses done on 152 plasma samples from 1982 obtained from physicians without prostate cancer. The researchers found that survey participants who later developed prostate cancer tended to have higher levels of IGF-I in their blood than did the controls. Men with IGF-I levels in the upper quartile (25 per cent) were found to have a 4.3 times greater risk of developing prostate cancer than did men with levels in the lower quartile of results. On average, there was a seven-year lag between the appearance of a high IGF-I level in the blood samples and the actual diagnosis of prostate cancer. The importance of high IGF-I levels was found to be particularly significant for men over 60 years of age. In this age group men with IGF-I levels in the highest quartile were almost eight times more likely to later develop prostate cancer than were men with levels in the lowest quartile. It is interesting to note that many of the men with elevated IGF-I levels who later developed prostate cancer had normal PSA levels (less than or equal to 4 ng/ml) when the blood samples were collected. The researchers conclude that IGF-I levels may serve as an early warning signal for prostate cancer in much the same way as high cholesterol levels serve as an early warning for atherosclerosis and heart disease. They also raise concern that administration of growth hormone and specifically IGF-I to delay the effects of aging in older men may increase the risk of prostate cancer. Other researchers (data still unpublished) have found an equally strong link between IGF-I levels and the risk of breast cancer and are currently investigating an association with colon cancer.
Chan, June M., et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science, Vol. 279, January 23, 1998, pp. 563-66
Barinaga, Marcia. Study suggests new way to gauge prostate cancer risk. Science, Vol. 279, January 23, 1998, p. 475

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